Because the kidney is important in the long term regulation of blood pressure and is the major organ involved in the regulation of sodium homeostasis, many studies have focused on abnormal renal handling of sodium chloride in the pathogenesis of essential hypertension. The autocrine/paracrine agents, dopamine and angiotensin II, work in an opposing manner to regulate renal function. Specifically, dopamine, via dopamine D1 and D3 receptors, is natriuretic while angiotensin II, via AT1 receptors, is antinatriuretic. Increased activity of the renin angiotensin system (RAS) and loss of function in the dopaminergic system lead to sodium retention and hypertension. We have reported that impairment of the renal D1 receptor in mice caused by overexpressing the G protein-coupled receptor kinase type 4 variant, GRK4 A142V, leads to high blood pressure. A similar mechanism may be operating in human essential hypertension; the GRK4 gene locus (chromosome 4p16.3) is linked to and GRK4 variants are associated with hypertension. GRK4 variants impair D1 receptor function in human renal proximal tubules. Expression of GRK4 variants in cell lines replicates the D1 receptor defect noted in renal proximal tubules. Inhibition of GRK4 function or expression normalizes D11 receptor function in and human renal proximal tubule cells/cell lines expressing GRK4 gene variants. Moreover, renal selective prevention of the expression of GRK4 in spontaneously hypertensive rats attenuates the development of hypertension. The overall goal of this PPG is to test the hypothesis that in genetic hypertension the reduction of D1 and D3 receptor function, caused by GRK4, cannot oppose AT1 receptor function leading to increased renal sodium reabsorption and high blood pressure. To accomplish our goal, we have organized a team of investigators, experienced in studies of dopamine and RAS, to elucidate the nature of their gene/gene interactions in health and in hypertension. Project by Felder will test the hypothesis that variant GRK4 proteins have increased constitutive activities that desensitize the D1 receptor but not the AT1 receptor. Project by Carey will test the hypothesis that salt sensitivity is produced when GRK4 variants desensitize the D1 receptor in the kidney, and that hypertension is produced when variants related to the RAS are also present. Project by Jose will test the hypothesis that renal proximal tubule sodium transport is regulated, in part, by an interaction among D1, D3, and AT1 receptors and that an aberrant interaction occurs in hypertension because of GRK4 variants. These gene/gene interactions are in keeping with the critical roles these receptors play in the polygenic causation of genetic hypertension.